Professor of Internal Medicine and Dermatology and Deputy Chair of the Department of Dermatology at MD Anderson Cancer Center
Would you briefly describe anaplastic large cell lymphoma?
Anaplastic large T-cell lymphomas (ALCL) of the skin appear as red or pink papules or nodules that grow quickly and ulcerate, often with formation of a black eschar (patch of dead skin). Nodules may spontaneously regress in about 25 percent of cases or they continue to grow and must be treated with local radiation or methotrexate or chemotherapy. Primary cutaneous ALCL (pc-ALCL) by definition begins in the skin in a patient with no prior history of mycosis fungoides. Pc-ALCL may later go to the regional lymph nodes or it can become systemic whereas systemic ALCL begins in the nodes and may involve the skin secondarily.
Pc-ALCL is on a spectrum with self-regressing lymphomatoid papulosis and together they are known to pathologist as CD30 positive lymphoproliferative disorders. Lymphomatoid papulosis (LYP) differs from pc-ALCL by its smaller papules (< 1.5 cm), that by definition always regress within several months. Systemic (nodal) ALCL can be divided into two groups: anaplastic lymphoma kinase (ALK) negative or ALK positive depending on whether there is expression of the nuclear ALK protein that makes the cells grow faster (a translocation). Pc-ALCL is almost always ALK negative, so ALK positive pc- ALCL must be evaluated for systemic involvement.
How common is ALCL?
ALCL is a relatively rare form of peripheral T-cell lymphoma (PTCL) compared to mycosis fungoides, whether in nodes or primary cutaneous. Skin ALCL has a good prognosis and favorable overall survival. For the systemic form, ALK-positive ALCL is found in younger patients and has a better prognosis than ALK-negative ALCL which is similar to PTCL - nos.
What are the main areas of research?
One major area in ALCL research is work being done on the epidemiology of all the subtypes of peripheral T-cell lymphomas. The frequency of various tumors types varies throughout the world, as shown by an ongoing international collaboration. For example, ALCL is a tumor found mainly in the west, while natural killer/T-cell lymphoma (nasal type) is a lymphoma found mainly in the east. Different locations in the world have different frequencies of these lymphomas. Pathologists are working intensely to classify lymphomas based on their immunohistochemistry and other biomarkers of disease. For ALCL as for other cancers, research is directed towards identifying biomarkers which can be used as targets for directed therapy. For ALCL the obvious markers are CD30 or ALK (for ALK positive systemic ALCL).
How is ALCL typically treated?
The treatment paradigm for systemic ALCL is changing. In the past, patients would have been treated with a regimen called CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone). Based on recent data with brentuximab vedotin showing a high response rate, it will likely be evaluated as front-line therapy for the disease. Methotrexate also has activity in treating primary cutaneous and systemic ALCL. In patients with skin ALCL, very low doses of methotrexate are sometimes effective, and some patients with ALCL have reported spontaneous regression of lesions. Radiation is also very active for treating localized tumors.
I would like to focus a bit on CD30, a surface receptor that belongs to the tumor necrosis factor family. CD30 was first described in Kiel, Germany. Brentuximab vedotin (Adcetris) is a conjugated human antibody to CD30 that is approved for the treatment of the relapsed or refractory form of systemic ALCL, based on the high response rates and high complete response rates that are durable. The antibody is not yet approved for the treatment of primary cutaneous ALCL but we are completing a Phase II trial evaluating the safety and efficacy of brentuximab vedotin. It has shown very promising results in patients with pc-ALCL, LYP as well as CD30 positive mycosis fungoides. There is also an international Phase II randomized trial of brentuximab vedotin versus physician’s choice (methotrexate or bexarotene) that is enrolling patients with ALCL or CD30 mycosis fungoides.
Overlap exists in the histology of CD30 ALCL tumors and CD30 mycosis fungoides. Whereas ALCL manifests with tumors which contain sheets of CD30 atypical lymphocytes, mycosis fungoides presents with patches, plaques, or tumors which contain epidermotropic memory T-cells with variable CD30 positive expression. Tumor stage mycosis fungoides can exist with or without large cell transformation as defined by having 25 percent of the lymphocytes having nuclei that are four times normal size. In a patient who has a history of classic patch and plaque mycosis fungoides, the emergence of a CD30 tumor is interpreted as CD30 mycosis fungoides whereas a CD30 positive tumor arising de novo or in the setting of lymphomatoid papulosus, would be called ALCL. CD30 mycosis fungoides is not currently considered to be included as part of the CD30 lymphoproliferative disorders. Of interest, we have observed that patients may currently have different lesions including LyP, patch plaque mycosis fungoides, and tumors all with CD30 positive expression and with the same T-cell receptor clonality. This suggests that the morphology of these lesions may depend on the density or location of the lymphocytes rather than clonal evolution, however this needs further study.
In our brentuximab vedotin study, responses were seen at any level of CD30 expression. How much CD30 is needed on the cell surface in order for brentuximab vedotin to be effective is a current ongoing research issue. This is of particular importance for patient advocacy groups like the Lymphoma Research Foundation (LRF) because the Food and Drug Administration is requiring the company that manufactures brentuximab vedotin to develop a kit to test for the presence of CD30. The manufacturer will have to designate an amount of CD30 required to be present on cells. There is concern that once a kit and a cut–off level for CD30 are developed, certain patients who may benefit from treatment with brentuximab vedotin may not be eligible based on their CD30 expression being too low. This has happened in the past. Insurance companies also can deny coverage because the biological treatments are costly. I think an important issue for patient advocacy is to make certain that targeted therapies are not restricted without evidence based studies.
Can you talk about the importance of clinical trials, and are there any specific trials you wish to discuss?
Clinical trials are absolutely necessary to move forward in the field of cutaneous lymphomas. Without patients willing to participate in clinical trials, there would not be new medicines developed for people to use. Often, the medications in clinical trials are superior to what is already approved. Recently, we have seen active drugs removed from the market leaving us reduced options for treating certain cancers or lymphomas. I am a strong advocate for clinical trial participation because I think that patients obtain an enormous benefit of access to a new drug that may be more efficacious than standard treatments.
What advice would you give a newly-diagnosed patient?
Regarding patients with pc-ALCL, the disease has a good prognosis, and treatment is based on disease extent and severity. If a patient has one or two nodules, we can radiate the nodules and sometimes the tumors self-regress. If the lesions are more dispersed throughout the body, we can use methotrexate or brentuximab vedotin, which is a newer option. This advice is reassuring for patients.
Would you recommend that a patient become involved with the Lymphoma Research Foundation?
I think that patients can obtain a great deal of information from patient advocacy groups like LRF. I encourage my patients to join groups like LRF because of the educational opportunities. Patients can help raise money for research and advocate for more funding of rare lymphomas through partnering with patient advocacy groups.
Updated June 19, 2013